The present invention relates to a method of preparing Form II crystals of clarithromycin comprising treating clarithromycin with water to provide said crystals having no residual organic solvent.
Clarithromycin, 6-O-methylerythromycin A, is a semisynthetic macrolide antibiotic of formula (I) which exhibits a wide range of antibacterial activity: 
It has been discovered that clarithromycin exists in two distinct crystalline forms, xe2x80x9cForm Ixe2x80x9d and xe2x80x9cForm IIxe2x80x9d, as described in International Publication Nos. WO 98/04573 and WO 98/04574. The crystal forms can be identified by infrared spectroscopy, differential scanning calorimetry and powder x-ray diffraction spectrophotometry. Form I crystals of clarithromycin are prepared by recrystallization from ethanol, tetrahydrofuran, isopropyl acetate, isopropyl alcohol or a mixture thereof. However, the thermodynamically more stable Form II is used in the drug formulations currently on the market.
Form II crystals of clarithromycin have been prepared by crystallization from chloroform/isopropyl ether (1:2) (see Merck Index 12th ed., pp. 395), but this method has a problem in that the resulting Form II crystals contain residual organic solvents. Alternatively, Form II crystals may be obtained by heating Form I crystals under a vacuum at 80xc2x0 C. or higher for a prolonged time (see International Publication No. WO 98/04573), but this method has the problem of low productivity.
International Publication No. WO 98/04574 teaches a method of preparing clarithromycin crystal Form II using various organic solvent systems or aqueous solvents containing water-miscible organic solvents. However, this method is hampered by a relatively low yield (approximately 9 to 83%) and still has the problem of entrained organic solvents.
Accordingly, there has existed a need to develop a new simple method for preparing pure Form II crystals of clarithromycin in a high yield.
Accordingly, it is a primary object of the present invention to provide pure Form II crystals of clarithromycin having no residual solvent in a high yield.
In accordance with the present invention, there is provided a method of preparing Form II crystals of clarithromycin comprising treating clarithromycin with water or with a mixture of water and a water-immiscible organic solvent.